The present invention relates to 1,2,4-triazole heterocyclic carbon compounds and to their preparation and use. More particularly, the invention relates to 2-[3-[4-(3-halophenyl)-1-piperazinyl]propyl]-5-(1-hydroxyethyl)-2,4-dihydr o-4-phenoxyalkyl-3H-1,2,4-triazol-3-ones and their therapeutic use in treating depression.
The tranquilizing compound known as etoperidone; chemically, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-4,5-diethyl-2H-1,2,4-triazo l-3(4H)-one, was disclosed by Palazzo in U.S. 3,857,845 which issued 12/1974. Etoperidone is depicted structurally below as (1) ##STR1## and has been studied clinically; cf: La Selva, et al., Riv. Neuropsichiat. Sci. Affini, 25/2, 57-68, 1979 (in Italian: English summary).
Etoperidone is in turn related to a series of 1,2,4-triazolo[4,3-a]pyridines of general formula (2) disclosed by Palazzo, et al., in U.S. Pat. No. 3,381,009 to exhibit tranquilizing action. ##STR2##
In the above structure R is hydrogen or methyl and R' is hydrogen, lower (C.sub.1-4) alkyl, lower alkoxy, or halogen. Pharmacological properties of one compound of this series in particular, trazodone; chemically, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridi n-3(2H)-one, have been described in more detail by Silvestrini, et al., International Journal of Neuropharmacology, 7, 587-599 (1968). Trazodone has been studied extensively in man and is currently marketed as an antidepressant agent which is equivalent in effectiveness to imipramine but having fewer side effects (Fabre, et al., Current Therapeutic Research, 25, 827-834 (1979)).
Also related is a series of compounds having structure (3) as disclosed by Temple, Jr., et al. in U.S. Pat. No. 4,338,317 which issued July 6, 1982. ##STR3##
In the above structure (3), R is halogen. The most preferred embodiment of this series is the compound of Formula (3) wherein R is meta-chloro; this compound being commonly known as nefazodone and is also referred to as MJ 13754. Currently, nefazodone is undergoing clinical study as an antidepressant agent under investigational new drug status.
It is of interest in regard to the compounds of the instant invention that a major metabolic pathway for both etoperidone and nefazodone involves alpha-carbon hydroxylation of the ethyl group located in the 5- position of the triazolone ring. This has been confirmed, for example, by comparison of metabolic isolates of nefazodone with the synthetically available corresponding 5-hydroxyethyl analog of the instant invention.
Attention is also called to pending application Ser. No. 06/509,266 which is a continuation-in-part of the U.S. Pat. No. 4,338,317 subject matter (nefazodone) and discloses a series of compounds including those depicted by structure (4) ##STR4## In the above structure, n is 2-4, R remains halogen, and R.sup.1 is hydrogen, halogen, alkoxy, or trifluoromethyl.